1. Field of the Invention
This invention relates to a novel class of heterocyclic compounds useful for selectively inhibiting chymotrypsin-like enzymes, selectively inhibiting elastase or for generally inhibiting serine proteases of all classes. This invention also relates to a method of treating inflammation in patients using the novel compounds of the present invention. We have found that isocoumarins substituted with hydrophobic groups are potent inhibitors of chymases and elastase, therefore they are useful as anti-inflammatory agents.
2. Description of the Related Art
Serine proteases play critical roles in several physiological processes such as digestion, blood coagulation, complement activation, fibrinolysis, viral infection, fertilization, and reproduction. Serine proteases are not only a physiological necessity, but also a potential hazard if they are not controlled. Uncontrolled proteolysis by elastases may cause pancreatitis, emphysema, rheumatoid arthritis, bronchial inflammation and adult respiratory distress syndrome. Human polymorphonuclear leukocyte elastase may also be involved in blistering. Accordingly, specific and selective inhibitors of these proteases should be potent anti-inflammatory agents useful in the treatment of protease-related diseases (Powers and Harper, in Proteinase Inhibitors, Barrett and Salvesen, eds., Elsevier, 1986, pp 55-152, incorporated herein by reference). In vitro proteolysis by chymotrypsin or the elastase family is a serious problem in the production, purification, isolation, transport or storage of peptides and proteins.
Anti-inflammatory agents were used to treat elastases-associated inflammation including rheumatoid arthritis and emphysema. Although the naturally occurring protease inhibitor, .alpha.1-protease inhibitor (.alpha.1-PI) has been used to treat patients with emphysema, this inhibitor is not widely used clinically due to the high dosage needed for the treatment and difficulty of producing large quantities. Therefore small molecular weight elastase inhibitors are needed for therapy.